DESCRIPTION (Applicant's Abstract): Stress, either of physical or psychological origin, has been implicated as a trigger for a number of devastating autoimmune and neuropsychiatric disorders, such as lupus erythematosus, depression, and schizophrenia. While we have a firm understanding of the physiology of the final common effectors involved in the stress response, i.e., corticotropin-releasing hormone and vasopressin, our knowledge of brain mechanisms activating the hypothalamic-pituitary-adrenal axis is more limited. Clearly, the glucocorticoids have powerful consequences associated with their hypersecretion during and after stress. However, the underlying neural mechanisms providing input to the neurons of the paraventricular nucleus are the substrates of neuropsychiatric illness. A more detailed understanding of the molecular and cellular relationships between neurotransmitters and neuromodulators in the regulation of hypothalamic-pituitary-adrenal axis secretions may provide keys to unlocking disorders, such as depression or schizophrenia or discoveries that may lead to new therapeutics for these disorders. Glutamate is the most abundant excitatory neurotransmitter in the neuroendocrine axis, and has been implicated in the etiology of schizophrenia, yet the physiological role of this excitatory amino acid transmitter is poorly understood in the regulation of the hypothalamic-pituitary-adrenal axis. One of the aims of the proposed studies is to characterize the molecular and cellular events elicited by excitatory amino acid receptor activation in the control of the secretions of the hypothalamic-pituitary-adrenal axis. Hypoglycemia, a well-characterized and readily controllable "metabolic stress," precipitates excitatory amino acid release in the brain. Consequently, another aim of these investigations is to employ molecular and neuroendocrinological techniques to explore the participation of excitatory amino acid receptor activation in the hypothalamic-pituitary-adrenal axis during hypoglycemia. These studies aim to reveal important new information about the regulation of stress hormone secretion by glutamate and may be significant in better understanding brain mechanisms in neuropsychiatric and other stress-related disorders.